AQ-AH 208, a new bradycardic agent, increases coronary collateral blood flow to ischemic myocardium

The effect of AQ-AH 208 [3,4-dihydro-6,7-dimethoxy-2-(3 - ((2-(3,4-dimethoxphenyl)ethyl)-amino- methyl)propyl)-1(2H)-isoquinolinone], a new selective bradycardic agent, on coronary collateral perfusion was investigated in anesthetized open-chest dogs following acute occlusion of the left anterior descending coronary artery. AQ-AH 208 (0.3 mg/kg i.v.), propranolol (0.3 mg/kg i.v.), and N-dimethylpropranolol (DMP; 2.5 mg/kg i.v.) were equieffective in reducing heart rate approximately 15%. AQ-AH 208 increased collateral flow to the subepicardium, midmyocardium, and subendocardium by 24, 46, and 35% (p less than 0.05), respectively, while propranolol and DMP had no effect. Atrial pacing to predrug levels in the presence of AQ-AH 208 reduced the increases in collateral flow to the different myocardial layers to 16, 25, and 30%, respectively; however, these increases were still significantly greater than control. It is concluded that part of the AQ-AH 208-induced increase in collateral perfusion is due to an increase in diastolic duration. The nature of the frequency-independent component of the effect is unknown but may be explained by a selective decrease in extravascular coronary resistance in the ischemic zone or an increase in the conductance of large epicardial coronary or collateral vessels.     

Comparison of the haemodynamic effects of the selective bradycardic agent UL-FS 49, with those of propranolol during treadmill exercise in dogs.

1. To clarify whether the bradycardic agent UL-FS 49 exhibits a positive inotropic effect even in the absence of improvement in regional myocardial function of an underperfused myocardial area, this study was undertaken in dogs with unimpaired coronary flow. 2. We also investigated the haemodynamic and functional effects of the negative chronotropic and inotropic beta-adrenoceptor blocker propranolol. 3. UL-FS 49 did not depress total or regional myocardial performance. Moreover, an increase in positive left ventricular dp/dt max at rest suggests a positive inotropic effect of UL-FS 49. 4. Propranolol, in contrast to UL-FS 49, led to a marked reduction in positive dp/dt max, stroke volume and systolic wall thickening at rest and during exercise. Additionally, propranolol decreased the exercise values of cardiac output, left ventricular work and left ventricular power to a far greater extent than UL-FS 49. 5. In contrast to propranolol, the selective bradycardic agent UL-FS 49 did not decrease total or regional ventricular performance and caused less reduction in cardiodynamic parameters during exercise. 6. These results suggest that patients with moderate coronary insufficiency or patients with coronary vessel disease and mild left ventricular failure may attain a higher exercise limit under selective bradycardia with UL-FS 49 in comparison to that possible with a beta-adrenoceptor antagonist, such as propranolol.     

Binding of two specific bradycardic agents, alinidine and AQ-A 39, to muscarinic receptors of guinea pig atria and ventricle

The mechanism of action of the two "specific bradycardic agents" alinidine and AQ-A 39 (falipamil) is still a matter of controversy. Their binding properties to atrial and ventricular myocardium of the guinea pig and rat were, therefore, investigated by the radioligand binding technique. In competition studies against the nonselective antagonists [125I]3-quinuclidinyl 4-iodobenzilate [( 125I]QNB) and 1-N-methyl-[3H]scopolamine methylchloride [( 3H]NMS), both alinidine and AQ-A 39 competitively displaced the radioligands with I50 values (corrected for radioligand concentration) of 1-2 microM (alinidine/[125I]QNB) and 4 microM (alinidine/[3H]NMS), respectively. The I50 values for AQ-A 39 were lower by a factor of two. Slope factors (pseudo Hill coefficients) were 0.7-0.8 (AQ-A 39) and 0.8-0.9 (alinidine), and significantly lower than unity in both atria and ventricle. The guanosine triphosphate (GTP) (100 microM) and 5'-guanylimido-di-phosphate [Gpp(NH)p] (100 microM) slightly creased [3H]QNB binding and produced no or only a small (factor 2-3) rightward shift of alinidine and AQ-A 39 competition curves. At high concentration (1 mM), AQ-A 39 drastically decreased [125I]QNB dissociation rate from both atrial and ventricular receptors (t1/2 control, 19 min; plus AQ-A 39, 75 min) while alinidine (1 mM) decreased dissociation half-life in ventricle with no change in atria. It is concluded that both bradycardic agents possess some but not all characteristics of weak agonists in binding studies, and that they also bind to an allosteric site of the muscarinic receptors. Association with this site could possibly activate a mixed Na+/K+ inward pacemaker current (if) resulting in bradycardia.     

Specific bradycardic agents. 2. Heteroaromatic modifications in the side chain of specific bradycardic benzazepinones: chemistry, pharmacology, and structure-activity relationships

Compound 1 (UL-FS 49) has recently been described as the representative of a novel class of antiischemic compounds termed "specific bradycardic agents". In search of specific bradycardic agents with different pharmacokinetic profiles, heteroaromatic analogues of 1 have been synthesized and evaluated for their bradycardic activity, selectivity, and duration of action. The chain length n and the nature of the heteroaromatic system of compounds 2 strongly determine the biological activities. Unsubstituted benzothiophenes and benzofurans in combination with a chain length of n = 2 give the most active bradycardic compounds. Some of the new compounds combine high bradycardic potency and selectivity with a short duration of action and may thus be useful for the development of short-acting specific bradycardic drugs.     

Electrophysiological effects of S 16257, a novel sino-atrial node modulator, on rabbit and guinea-pig cardiac preparations: comparison with UL-FS 49.

1. S 16257 is a new bradycardic agent. Its electropharmacological profile has been compared to that of the known bradycardic compound UL-FS 49 (Zatebradine). Intracellular recordings of action potentials (APs) were performed with conventional glass microelectrodes. 2. In the rabbit isolated sino-atrial node (SAN) tissue, S 16257 and UL-FS 49 (1 microM, 3 microM and 10 microM) were equipotent in slowing spontaneous APs firing predominantly by decreasing the rate of diastolic depolarization (at 3 microM, -23.8 +/- 3.9% and -27.9 +/- 2.6%, respectively). For the two compounds a maximal effect was obtained at 3 microM. In these preparations, action potential duration at 50% of total repolarization (APD50) was more affected by UL-FS 49 than S 16257 at any concentration tested (at 3 microM, +8.9 +/- 2.9% and +29.1 +/- 3.7% for S 16257 and UL-FS 49, respectively; P < or = 0.01). 3. To estimate the direct effects on AP duration, driven cardiac preparations were exposed to these agents. In guinea-pig papillary muscles, paced at a frequency of 1 Hz, increasing concentrations of S 16257 or UL-FS 49 (0.1 to 10 microM, 30 min exposure for each concentration) slightly prolonged AP repolarization. This prolongation was more marked for UL-FS 49 (at 1 microM, +6.1 +/- 0.6% and +11.2 +/- 1.3% elevation of APD50, for S 16257 and UL-FS 49, respectively). 4. Application of UL-FS 49 (3 microM) to rabbit Purkinje fibres, triggered at a frequency of 0.25 Hz, induced a marked prolongation of APD50 and APD90 (+149.4 +/- 51.2% and +86.0 +/- 15.4%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Use- and frequency-dependent blockade by UL-FS 49 of the if pacemaker current in sheep cardiac Purkinje fibres

The mechanism by which the bradycardiac agent UL-FS 49 blocks the if pacemaker current was investigated in sheep Purkinje fibres using the two microelectrode voltage-clamp technique. If was activated by 1 s pulses applied between -30 mV and -120 mV at 0.4 Hz in a modified Tyrode solution containing BaCl2 and MnCl2, and with TRIS replacing most of the Na+. UL-FS 49 caused an exponential decline of the if current amplitude during a train of pulses. Both the rate and extent of the if reduction increased with drug concentration, without there being a resting blockade. Recovery from blockade followed a single exponential time course during prolonged hyperpolarizations. The recovery rate was extremely slow and increased with more negative voltages, as did the extent of steady state recovery from blockade. A frequency-dependent reduction of the diastolic depolarization rate resulted from a use-dependent blockade of the pacemaker current.     

Actions of pyridostigmine and organophosphate agents on chick cells,mice, and chickens

Gulf War veterans were given pyridostigmine bromide (PB) tablets to enhance the therapeutic effect of antidotes to nerve agents in the event of exposure. The goal of this research is to examine whether combined exposure to PB and sarin (agent GB) is more neurotoxic to sensitive surrogate animals, mice and chickens, than if given separately. Scoping trials were performed to establish appropriate dose-response ranges for sarin and control chemicals. IC50 values were determined in chickens and mice for in vitro inhibition of acetylcholinesterase (AChE) and neuropathy target esterase (NTE). The results indicated PB neither inhibits NTE nor does it spare sarin's inhibition of AChE. Chick embryo nerve cells in vitro showed more inhibition of AChE activity and no faster recovery when PB treatment was followed by DFP treatment than the other way around. Experiments on chickens also indicated that PB treatment did not inhibit NTE and that it crossed the blood brain barrier inhibiting brain AChE although to a lesser extent than it inhibited blood cholinesterases. Other experiments determined multiple dose levels in chickens for sarin and DFP that inhibited > 80% of NTE, considered a threshold for triggering organophosphate-induced delayed neuropathy.     

地奥心血康对心肌缺血再灌注犬的心肌细胞膜结构与功能的影响

１６只成年杂种犬复制心肌缺血再灌注模型，分为地奥心血康（ＤＡＸＸＫ）治疗组和生理盐水（ＮＳ）对照组。结果表明，ＤＡＸＸＫ组血清胞内酶（ＡＳＴ，ＣＫ和ＬＤＨ）水平的增高低于ＮＳ组；心肌细胞膜Ｎａ＋，Ｋ＋－ＡＴＰ酶和Ｍｇ２＋－ＡＴＰ酶比活性高于ＮＳ组；心肌细胞膜ＬＰＯ含量低于ＮＳ组；心肌组织ＳＯＤ水平高于ＮＳ组。心肌电镜观察显示，ＤＡＸＸＫ可维持心肌细胞膜的完整性。＊Ｐ＜０．０１。图２ＤＡＸＸＫ组心肌细胞超微结构（×１２０００倍）细胞膜完整，肌原纤维排列整齐，少数线粒体稍肿胀讨论随着溶栓等疗法的成功应用，发现缺血再灌注可造成组织损伤［６］。寻找有效的抗缺血再灌注损伤的药物，可减轻其对组织损伤的程度。我们的实验证明，ＤＡＸＸＫ可明显降低血清酶水平，在一定程度上保持了膜结构的完整性。心肌超微结构的观察也证明了这一点。心肌缺血再灌注情况下，氧自由基对生物膜的损伤起了很重要的作用［７］。本实验发现，ＤＡＸＸＫ组心肌细胞膜ＬＰＯ含量明显低于ＮＳ组，与维持细胞内环境稳定有关的Ｎａ＋，Ｋ＋－ＡＴＰ酶、Ｍｇ２＋－ＡＴＰ酶比活性，ＤＡＸＸＫ组高于ＮＳ组，并且，Ｎａ＋，Ｋ＋－ＡＴＰ酶比活性与ＬＰＯ含量呈显著的负相关关系。提示由氧自?     

Neosordarin and hydroxysordarin,two new antifungal agents from Sordaria araneosa

Two novel antifungal agents belonging to the sordarin family have been isolated from fermentations of Sordaria araneosa by bioassay-guided purification and their structures elucidated by NMR techniques. Neosordarin (1) is closely related to the recently discovered hypoxysordarin (2), with only small differences on the aliphatic side chain acylating the hydroxyl in the 3'-position of the sordarose moiety. Hydroxysordarin (3) closely resembles sordarin (4), the only slight difference being the replacement of sordarose with altrose as the sugar unit.     

Effects of selective cyclooxygenase-2 and nonselective cyclooxygenase inhibition on myocardial function and perfusion

Nonselective nonsteroidal anti-inflammatory drugs and selective cyclooxygenase-2 (COX-2) inhibitors are purported to increase adverse cardiovascular events. We hypothesized that COX-2 inhibitors would alter myocardial blood flow, microvascular reactivity, oxidative stress, and prostaglandin levels. Adult Yorkshire swine were divided into 3 groups: no drug (control, n = 7), a nonselective COX inhibitor (naproxen 400 mg daily, NAP, n = 7), or a selective COX-2 inhibitor (celecoxib 200 mg daily, CBX, n = 7). After 7 weeks, physiologic measurements were taken and tissue harvested. Animals in the CBX group demonstrated significantly higher blood pressure and rate-pressure product. The NAP and CBX groups demonstrated an increased microvascular contraction response to serotonin. The NAP group showed increased myocardial levels of thromboxane and lower levels of prostacyclin. Levels of protein oxidative stress were increased in the CBX group. Myocardial apoptosis was lowest in the NAP group. Immunoblotting demonstrated decreased vascular endothelial growth factor and phosphorylated endothelial nitric oxide synthase expression in the NAP and CBX groups. Myocardial tumor necrosis factor-α was increased in both treated groups. Immunostaining for thromboxane A2 synthase and receptor demonstrated expression within the vascular smooth muscle and no observable differences between groups. Nonselective and selective COX inhibition does not alter myocardial perfusion but results in altered myocardial and vascular physiology that may have implications regarding cardiovascular risk.     

Three different bradycardic agents, zatebradine, diltiazem and propranolol, distinctly modify heart rate variability and QT-interval variability

Zatebradine, diltiazem and propranolol are all antiarrhythmic agents, and all induce bradycardia, but each is known to have a different initial molecular mechanism: zatebradine is a channel blocker of the hyperpolarization-activated inward current (I(f)); diltiazem is a blocker of the L-type Ca(2+) channel (I(CaL)), and propranolol is a beta-blocker. To further investigate the mechanisms underlying their clinical effects, we studied their effects on heart rate variability (HRV) and QT-interval variability (QTV). To this end, guinea pigs were treated with either zatebradine (1.5 mg/kg, i.p.), diltiazem (40 mg/kg, i.p.) or propranolol (20 mg/kg, i.p.). A dose of each agent that decreased HR by 20-22% was used in this study. HRV and QTV were analyzed by a fast Fourier and/or a wavelet transform algorithm. Zatebradine, an I(f) channel blocker, had no significant effect on HRV and QTV. Diltiazem, a non-dihydropyridine I(CaL) blocker, increased high frequency (HF) power and decreased the power ratio of the low frequency (LF) range to the HF range (L/H) in HRV, and increased QTV. Propranolol, a non-selective beta-antagonist, decreased LF power and L/H ratios in HRV, and appreciably reduced QTV. These differences in pharmacological action may help us better understand the antiarrhythmic and/or proarrhythmic actions of these agents when they are used clinically for reducing HR.     

Effects of the two enantiomers, S-16257-2 and S-16260-2, of a new bradycardic agent on guinea-pig isolated cardiac preparations.

1. The electromechanical effects of two enantiomers, S-16257-2 (S57) and S-16260-2 (R60), were studied and compared in guinea-pig isolated atria and ventricular papillary muscles. The possible stereoselectivity of the interaction on the cardiac Na+ channel was analysed by comparing the effects of the two enantiomers on the onset and recovery kinetics of the frequency-dependent Vmax block. 2. In spontaneously beating right atria, S57 and R60 (10(-8)M-10(-4M) exerted a negative chronotropic effect (pIC50 = 5.07 +/- 0.19 and 4.76 +/- 0.18, respectively) and prolonged the sinus node recovery time, this effect being more marked with S57. In electrically driven left atria, S57 decreased (P < 0.05) contractile force only at 10(-4M) and R60 at concentrations > or = 5 x 10(-5M), whereas in papillary muscles the negative inotropic effect appeared at concentrations > 10(-5M). 3. In papillary muscles driven at 1 Hz, S57 and R60 at concentrations higher than 5 x 10(-6M) produced a concentration-dependent decrease in the maximum upstroke velocity (Vmax) and amplitude of the cardiac action potential without altering the resting membrane potential or the action potential duration. S57 and R60 had no effect on the characteristics of the slow action potentials elicited by isoprenaline in ventricular muscle fibres depolarized in high K+ (27 mM) solution. 4. At 5 x 10(-5M), S57 and R60 produced a small tonic Vmax block. However, in muscles driven at rates between 0.5 and 3 Hz both enantiomers produced an exponential decline in Vmax (frequency-dependent Vmax block) which augmented at higher rates of stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)     

黄芪皂苷Ⅳ对缺血大鼠心肌钙运转和心功能的影响(英文)

目的:研究黄芪皂苷IV(XGA)对缺血大鼠心肌钙运转和心功能的影响.方法:84只Wistar大鼠分为3组:对照组(12只);缺血组(12只),皮下注射异丙肾上腺素(30 mg/kg);XGA组(60只),皮下注射异丙肾上腺素后给予XGA.测定大鼠血流动力学指标、心脏功能和心肌细胞内外钙的变化,观察XGA对缺血大鼠心肌钙运转和心功能的量-效和时-效关系.结果:给予XGA后缺血大鼠心功能和血流动力学明显改善,随着XGA剂量的增加和XGA作用时间的延长,缺血大鼠的心输出量、心率、每博量、平均动脉压、动脉收缩压、左心室搏出功、左室和右室收缩末期压力和右心室的 dp/dt逐渐恢复到对照组水平;给予XGA后心肌细胞游离钙和心肌组织总钙与缺血组比较明显下降,而红细胞膜钙泵活性较缺血组明显增加,但心肌细胞游离钙和心肌组织总钙下降的幅度及红细胞膜钙泵活性增加的幅度并没有随XGA剂量的增加而增加;随XGA作用时间的延长,心肌细胞游离钙逐渐下降.结论:XGA能够明显改善缺血大鼠的心功能,减少心肌细胞内过多的钙积聚是其作用机制之一.     

黄芪皂苷IV对缺血大鼠心肌钙运转和心功能的影响

目的：研究黄芪黄苷IV（XGA）对缺血大鼠心肌钙运转和心功能的影响。方法：84只Wistar大鼠分为3组：对照组（12只）;缺血组（12只）,皮下注射异丙肾上腺素（30mg/kg);XGA组（60只）,皮下注射异丙肾上腺素后给予XGA,测定大鼠血流动力学指标、心肌功能和心肌细胞内外钙的变化,观察XGA对缺血大鼠心肌钙运转和心功能的量－效和时－效关系。结果：给予XGA后缺血大鼠心功能和血流动力学明显改善,随着XGA剂量的增加和XGA作用时间的延长,缺血大鼠的心输出量、心率、每博量、平均动脉压、动脉收缩压、左心室博出功、左室和右室收缩末期压力和右心室的 dp/dt逐渐恢复到对照组水平;给予XGA后心肌细胞游离钙和心肌组织总钙与缺血组比较明显下降,而红细胞膜钙泵活性较钙血组明显增加,但心肌细胞游离钙和心肌组织总钙下降的幅度及红细胞膜钙泵活性增加的幅度并没有XGA剂量的增加而增加;随XGA作用时间的延长,心肌细胞游离钙逐渐下降。结论：XGA能够明显改善缺血大鼠的心功能,减少心肌细胞内过多的钙积聚是其作用机制之一。     

Effect of antihypoxic agents on the blood supply and function of the intact and ischemic myocardium

It was established in experiments on cats anesthesized with nembutal that the antihypoxic drugs sodium hydroxybutyrate, piracetam and glio-6 increased blood outflow from the coronary heart sinus. This was accompanied by a rise in the content of oxyhemoglobin in coronary venous blood. Sodium hydroxybutyrate was shown to exhibit the highest and most prolonged effect. On the contrary, the effect of glio-6 did not last long. All the antihypoxic drugs enhanced myocardial contractility without changing or slightly reducing the pulse rate. In experimental acute coronary circulation failure (temporary occlusion of the coronary artery with the recording of the epicardial electrogram), sodium hydroxybutyrate and, to a lesser degree, piracetam were discovered to improve the function of the focus of myocardial ischemia. A single administration of glio-6 did not affect the focus of acute myocardial ischemia.     

无创肢体缺血预适应对心肌缺血/再灌注损伤内皮功能的影响

目的研究无创肢体缺血预适应(limb ischemic preconditioning,LIPC)减轻心肌缺血/再灌注(ischemia/reperfusion,I/R)损伤的保护作用及其作用机制。方法健康♂Wistar大鼠随机分为I/R组、I/R+LIPC组、I/R+5羟基癸酸钠(5-hydroxydecanoate,5-HD)组及I/R+LIPC+5-HD组。I/R+LIPC组和I/R+LIPC+5-HD组连续3 d经历左后肢缺血预适应。d 4,全部动物经历心肌I/R损伤。I/R+5-HD组和LIPC+5-HD组于缺血前及I/R期间给予ATP敏感性钾通道阻断剂5-HD。结果与I/R组比较,LIPC缩小心肌梗死范围(P<0.05),降低心肌细胞凋亡指数(P<0.01),减少Fas、Fas L阳性细胞数(P<0.01),减少血清一氧化氮/内皮素-1比值降低的程度(P<0.05)。5-HD取消LIPC诱导的上述保护作用。与正常对照比较,心肌组织mir-30a-3p的表达在I/R组增加(P<0.01),在LIPC组减少(P<0.01)。结论LIPC可减轻心肌I/R损伤,改善内皮功能,其机制可能与开放ATP敏感性钾通道、调节血中一氧化氮与内皮素-1之间的平衡、减少心肌组织mir-30a-3p表达有关。